ABSTRACT Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. The greatest known risk factor for AD is increasing age; the majority of people with AD are age 65 and older. AD is a progressive disease, with dementia symptoms gradually worsening over several years. Current AD treatments cannot stop disease progression, but they can temporarily slow the progression of dementia symptoms and improve quality of life for those with AD and their caregivers. Our studies identified miRNAs in cerebrospinal fluid (CSF) from living donors that discriminate patients with AD from neurologically normal controls. We discovered 36 candidate miRNA biomarkers for AD in CSF from one cohort of donors, then validated 26 AD miRNA biomarkers in a new and independent cohort of CSF donors. We are focused on 17 of these biomarkers based on their performance in multi-marker models. Our goals here are 3-fold: (1) to establish the utility and short-term stability of the AD miRNA biomarkers in plasma; (2) to show that plasma miRNAs predict progression of AD in at-risk individuals; and (3) to determine the specificity of plasma miRNAs for AD vs. other dementias. Regarding goal 1, here we present new preliminary data that the CSF-derived AD miRNAs are robustly detected in plasma, and that results from quantitative PCR in plasma are more precise and reliable at detecting AD, have a lowered cycle threshold range, and show improved accuracy and amplification vs. CSF. Further, given that the miRNA biomarkers were first identified in CSF, which directly bathes the brain, their presence in plasma suggests that they are derived from and represent changes in the brain in AD. We will leverage our access to the corresponding plasma samples for the same patients, donated on the same date, that were used for the CSF validation studies. Regarding goal 2, we will examine the predictive power of the miRNAs for AD. We will leverage samples collected in a 3-year clinical study in which patients diagnosed with mild cognitive impairment donated plasma at baseline, and at the end of the study, to examine miRNAs in patients who progressed to AD vs. those that did not. Regarding goal 3, we will examine the specificity of the plasma miRNAs for AD vs. other dementias. Here we provide new preliminary data that the miRNAs distinguish AD from Parkinson?s disease (PD) and controls in CSF samples. We will extend these studies to examine the miRNAs in plasma from AD and PD patients, and in plasma from patients with Lewy body dementia and frontotemporal dementia. Together these studies will establish the CSF-derived miRNAs as biomarkers for AD in plasma, determine their predictive value for AD, and establish their level of specificity for AD vs. other dementias.